Review
Ellagitannins, ellagic acid and vascular health

https://doi.org/10.1016/j.mam.2010.09.005Get rights and content

Abstract

Hydrolysable tannins are phenolic phytochemicals that show high antioxidant and free-radical scavenging activities. For this reason their potential effects preventing oxidative related diseases, such as cardiovascular diseases, have been largely studied. In vitro studies show that ellagitannins, at concentrations in the range 10–100 μM, show some relevant anti-atherogenic, anti-thrombotic, anti-inflammatory and anti-angiogenic effects, supporting the molecular mechanisms for the vascular health benefits. While there is good evidence supporting the vascular effects in vitro, the evidence on animal models or humans is much scarcer. The in vitro results often do not match the findings in the in vivo studies. This could be explained by the low bioavailability of the antioxidant ellagitannins and ellagic acid. The main ellagitannin metabolites circulating in plasma are ellagic acid microbiota metabolites known as urolithins, and they have lost their free-radical scavenging activity. They are present in plasma as glucuronide or sulphate conjugates, at concentrations in the nM range. Future studies should focus in the bioavailable metabolites, urolithins, and in the form (conjugated with glucuronic acid or sulphate) and concentrations (nM range) in which they are found in plasma. In this review we critically discuss the role of ellagitannins and ellagic acid on vascular health.

Introduction

Walnuts and pomegranates consumption has been associated with cardiovascular health benefits. Both contain relevant amounts of phenolic antioxidants, and particularly ellagitannins (ETs) that have been considered responsible, at least partly, of these physiological properties (Espín et al., 2007a). These polyphenols are included into the category of hydrolysable tannins. Hydrolysable tannins are phytochemicals of the non-flavonoid polyphenol group, that include ETs, which release ellagic acid (EA) upon hydrolysis and under the physiological conditions of the gastrointestinal tract (GI), and gallotannins (GTs), which release gallic acid (GA). These phytochemicals show biological effects in vitro that have been connected to pharmacological (ET-rich medicinal plants) and nutritional (ET-rich foods) effects in vivo. These are mainly related to the fight and prevention of cardiovascular diseases and cancer. It has been suggested that the in vivo biological effects may be partially due to the high free-radical scavenging activity that these compounds exert when evaluated using in vitro assays. Many nutraceuticals, medicinal plant extracts and food products containing hydrolysable tannins, and particularly ETs, are currently commercialized and consumed due to their potential benefits on cardiovascular health. In the present study we review the current knowledge regarding the effects of ETs and EA on vascular health, and the bioavailability and metabolism of these phytochemicals in humans, as an essential mechanism to understand the medicinal significance of these antioxidant phytochemicals.

Section snippets

Chemistry and dietary burden

Plant hydrolysable tannins are known since ancient times due to their use in the process or leather tanning. Chemically they are different combinations of GA and hexahydroxydiphenic acids with glucose. Upon hydrolysis they release GA and EA (Fig. 1).

Many plant species containing ETs have been used for the treatment of diseases, particularly in Asia (Okuda et al., 2009). These include Agrimonia pilosa (agrimoniin), Camelia japonica (camelliatannin A), Cornus officinalis (cornussin A), Geranium

Bioavailability and metabolism

Understanding the absorption and metabolism of EA and ETs is essential to evaluate their potential medicinal effects on vascular health. The evidence available is supported on different studies using in vitro assays, animal models and human intervention trials.

In vitro digestion simulation studies have shown that in general, ETs are quite stable under the physiological conditions of the stomach. The acidic conditions (HCl, pH 1.8–2.0) and the stomach enzymes do not hydrolyze the original ETs

In vitro studies related to potential benefits of hydrolysable tannins against cardiovascular diseases

Atherosclerosis constitutes the etiological base of cardiovascular diseases and is linked to oxidative stress (Kaneto et al., 2010). Although fruit and plant extracts rich in EA, GA and (or) hydrolysable tannins have been repeatedly reported to exert strong antioxidant effects (Serrano et al., 2009, Basu and Penugonda, 2009), description of the antioxidant properties of these compounds is out of the scope of this review. Atherosclerosis is also a very complex chronic disorder caused by multiple

Studies on animal models

Early work on EA dates back to the 60s. In these studies EA was used intravenously, resulting in a hypercoagulable state in rats, dogs, cats and rabbits (Girolami et al., 1966, Cliffton et al., 1966). One year later Gautvik and Rungsted (1967) first described a hypotensive effect of EA in rats after i.v. administration and the formation of kinin from plasma kallikrein. McKay et al. (1969) reported in rabbits and monkeys that EA inhibited fibrinolysis and activated Hageman factor (coagulation

Human intervention studies

Despite the huge output of in vitro studies regarding the potential activities of ETs and EA in relation to cardiovascular diseases, the scientific evidence derived from human intervention studies is, however, much more limited.

The role of EA in cardiovascular-related topics such as haemostasis was suggested by Ratnoff and Crum (1964) who reported the in vitro activation of the Hageman factor. Soon after, Botti and Ratnoff (1964) described the hypercoagulable state induced by the intravenous

Final remarks

Any systemic potential activity attributed to a dietary compound involves its absorption and delivery to the target tissue in its intact form (as ingested compound) or as active metabolite. The specific role (if any) of ETs in cardiovascular protection is not known yet. Their bioavailability (absorption to the blood flow and further detection in urine) is very poor, and thus a number of possibilities can arise to explain the possible cardiovascular effects attributed to these molecules:

  • The

Acknowledgments

This work has been supported by the Projects CICYT-BFU2007-60576 and Consolider Ingenio 2010, CSD2007-00063 (Fun-C-Food).

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